1. Technical Field
The present invention relates to an optical assembly and method for determining the concentration of an analyte in body fluid and particularly, but not exclusively, to an optical assembly and method for determining the concentration of glucose in body fluid.
2. Related Art
Diabetes mellitus, which is commonly known as diabetes, is the name for a group of chronic diseases that affect the way the body uses food to make the energy necessary for life. Diabetes is primarily a disruption of carbohydrate metabolism with the result that the blood glucose level of a person may vary considerably, from 40 mM (720 mg/dl) to as low as 1 mM (18 mg/dl). In comparison, the blood glucose level of a person without diabetes varies very little, remaining between 4 mM and 8 mM.
In the management of diabetes via insulin, the regular measurement of glucose in the blood is essential in order to ensure a correct administration of insulin. Furthermore, it has been demonstrated that in the long term care of the Type I and Type II diabetic patient, better control of the blood glucose levels can delay, if not prevent, the onset of retinopathy, circulatory problems and other degenerative diseases often associated with diabetes. The majority of diabetes care is self care, and so there is a need for reliable and accurate self-monitoring of blood glucose levels by diabetic patients, since it is essential for the day-to-day care of Type I and Type II diabetes.
Since the late 1970s an increasing number of diabetic patients have been measuring their own blood glucose concentrations using “finger-prick” capillary blood samples. Self blood glucose monitoring is used by Type I diabetics in the home to detect hypoglycemia and hyperglycemia, and therefore to determine the corrective action required, such as taking extra food to raise the blood glucose concentration or extra insulin to lower the blood glucose concentration. These measurements, which are made using low-cost, hand-held blood glucose monitors, also allow the physician to adjust the insulin dosage at appropriate times so as to maintain near normoglycemia. In Type II diabetes, self blood glucose monitoring is used to inform newly diagnosed non-insulin dependent patients about their condition, how to manage it and to monitor themselves with daily or weekly readings as necessary.
These blood glucose monitors use either reflective photometry or an electrochemical method to measure blood glucose concentration. The finger or earlobe of the patient is typically pricked with a sterile lancet and a small sample of blood is placed on the test strip. After analysis, the monitor displays the blood glucose concentration. The main disadvantages of self blood glucose monitoring systems are poor patient acceptance because the technique is painful, only intermittent assessment of diabetic control is possible and readings during the night or when the patient is otherwise occupied are not possible.
The US National Institute of Health has recommended that blood glucose testing should be carried out by Type I diabetic patients at least four times a day, a recommendation that has been endorsed by the American Diabetes Association. This increase in the frequency of blood glucose testing imposes a considerable burden on the diabetic patient, both in financial terms and in terms of pain and discomfort. Thus, there is clearly a need for a better long-term glucose monitoring system that does not involve drawing blood from the patient.
There have been a number of proposals for glucose measurement techniques that do not require blood to be withdrawn from the patient. Many of these methods measure blood glucose concentration using near infrared (NIR) spectroscopy to analyse the glucose concentration in the blood vessels in the skin. For example, U.S. Pat. Nos. 5,028,787 and 5,362,966 describe devices for measuring glucose concentration in a fingertip on passing NIR light (0.6 μm-1.1 μm) light through the finger to the detector, and a similar device that measures the glucose concentration in a vein by shining NIR light on to one part of the vein in the wrist and detecting the light emerging from another part of the vein nearer the elbow. Disadvantages of the use of NIR spectroscopy are that the measurement suffers from interference by other optical absorbers in the tissue and is also dependent on blood flow in the skin. The absorbance peaks of water at these wavelengths are variable in position with temperature such that shifts in water absorbance induced by temperature changes of less than a degree are greater than those induced by a 20 mg/dl variation in glucose concentration.
It has been observed that the concentration of analytes, such as glucose in subcutaneous fluid correlates with the concentration of those analytes in the blood. There have been several techniques developed for measuring the glucose concentration in the tissue; examples include subcutaneous implants containing glucose binding assays, such as that described in W091/09312, in which the degree of binding of the assay component to glucose is indicated by the intensity of fluorescence produced by the assay. This type of device is minimally invasive, as the fluorescence signal is able to be read remotely and so the extraction of a blood sample is avoided, but it does require an invasive operation to install the implant. Therefore, it is apparent that there is a need for an improved method of glucose concentration measurement that may be used regularly by a diabetic patient in the home, which is cheap and simple to use, as well as being accurate and non-invasive in nature.
It is known that an optical waveguide, such as a plate, a prism, or optical fibre may pass light along its length by the process of total internal reflection. In the case of a prism, total internal reflection occurs when the angle of incidence of the light entering the prism exceeds the critical angle,
      θ    ⁢                  ⁢    c    ⁢          :        ⁢                  ⁢          θ      c        =            sin              -        1              ⁡          (                        n          2                          n          1                    )      where n2 is the refractive index of the region outside the prism, and n1 is the refractive index of the prism. At each reflection within the prism, an evanescent wave penetrates a small distance into the surrounding medium. It is therefore possible to obtain an absorption spectrum for the regions of the surrounding medium in contact with the outer surface of the prism, by comparing the light incident upon the prism with that emerging therefrom. This technique is known as attenuated total reflectance (ATR) spectroscopy. The signal-to-noise ratio for the absorption spectrum increases with the number of reflections within the waveguide achieved with evanescent wave interaction with the absorbent before detection of the emerging light. The use of a material with a high refractive index for the prism is therefore preferred, as this minimizes the critical angle θC and thereby maximizes the possible number of reflections back and forth through the waveguide, as the light travels along the waveguide.
A conventional ATR arrangement is illustrated in FIG. 1 of the drawings. The substance to be investigated (e.g. tissue) has a lower refractive index than the ATR element 10 which typically is made of ZnSe or diamond (n=2.4). In the absence of absorbance and for angles of incidence of the incident light 11 greater than the critical angle, total internal reflection occurs. However, when an absorbing material 12 is placed on the surface of the prism 10, an evanescent wave (not shown) is found to penetrate into the material and this evanescent wave is found to attenuate the total internal reflection.
The intensity I of a wave on passing through a distance t in an absorbing material is known to follow Beer's Law, which states:I=I0exp(−μt)where I0 is the intensity at the surface of the material and μ is the linear absorption coefficient, which can be expressed in terms of k, an extinction coefficient by:μ=4πk/λwhere λ is the wavelength of the light in air.
The behaviour of light in an absorbing material in which both refraction and absorbance occur can be expressed as a complex refractive index given by:ñ=n+ik where i is the √(−1) and ensures that the effect of k is to attenuate the light. Without i, k would simply add on to n and cause additional refraction. Thus, the optical behaviour of such a medium is completely expressed by ñ, the complex refractive index.
Interstitial fluid, namely the fluid disposed between cells within a tissue sample is known to have a glucose concentration that correlates with the blood glucose concentration. Referring to FIG. 2 of the drawings, the maximum sensitivity to analyte absorbance within a tissue sample occurs at or just greater than the critical angle. If the angle is reduced, ATR becomes insensitive to the analyte, i.e. no measurement of analyte concentration is possible.
Referring to FIG. 3 of the drawings, the penetration depth δ of the wave into the absorbing material, namely the depth to which an electric field associated with the evanescent wave decays to 1/e (approx 37%) of the value at the surface of the material, reduces significantly as the incident angle increases to the critical angle and beyond. In order to interrogate the interstitial fluid in the epidermis optically it is therefore necessary to penetrate beyond the stratum corneum.
Fingertips typically have stratum corneum thickness of up to 400 μm. However, at the critical angle the value of δ is typically only 3 μm so that the effective penetration depth for most subjects is insufficient for making a measurement of analyte concentration. Accordingly, it is only by going to reduced angles that the effective depth is significantly increased; however, as stated above, there is no sensitivity to analyte concentration at angles less than the critical angle. It is for these reasons that conventional ATR cannot measure glucose and other analyte concentration in the majority of subjects non-invasively.